2r3f

From Proteopedia

Revision as of 16:44, 21 February 2008

Crystal Structure of Cyclin-Dependent Kinase 2 with inhibitor

Overview

CDK2 inhibitors containing the related bicyclic heterocycles pyrazolopyrimidines and imidazopyrazines were discovered through high-throughput screening. Crystal structures of inhibitors with these bicyclic cores and two more related ones show that all but one have a common binding mode featuring two hydrogen bonds (H-bonds) to the backbone of the kinase hinge region. Even though ab initio computations indicated that the imidazopyrazine core would bind more tightly to the hinge, pyrazolopyrimidines gain an advantage in potency through participation of N4 in an H-bond network involving two catalytic residues and bridging water molecules. Further insight into inhibitor/CDK2 interactions was gained from analysis of additional crystal structures. Significant gains in potency were obtained by optimizing the fit of hydrophobic substituents to the gatekeeper region of the ATP binding site. The most potent inhibitors have good selectivity. (c) 2007 Wiley Periodicals, Inc. Biopolymers, 2007.

About this Structure

2R3F is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Cyclin-dependent kinase, with EC number 2.7.11.22 Full crystallographic information is available from OCA.

Reference

Structure-guided discovery of cyclin-dependent kinase inhibitors., Fischmann TO, Hruza A, Duca JS, Ramanathan L, Mayhood T, Windsor WT, Le HV, Guzi TJ, Dwyer MP, Paruch K, Doll RJ, Lees E, Parry D, Seghezzi W, Madison V, Biopolymers. 2007 Oct 15;. PMID:17937404

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